During therapy of advanced Parkinsons disease (PD) is unsatisfactory. Patients suffer from motor fluctuations ranging from severe off periods too uncontrolled abnormal movements. Replacing destroyed dopamine cells and nerve terminals with transplants of embryonic mesencepahlon may restore regulated release of dopamine and provide more normal motor control. For the past 3 years, using a double-blind placebo-controlled surgery protocol, we have implanted embryonic mesencephalic tissue containing dopamine cells into the brains of patients with advanced PD. Forty patients under age 75 with PD of at least 7 years duration were randomly assigned to either tissue implants or placebo surgery. Groups were matched for age, gender, and disease severity and were stratified by age. Patients and their examining physicians at Columbia University in New York (CPMC) have been blind to the treatment. After 3 months of baseline evaluations including two inpatient admissions at CPMC, diaries, home videotaping, and fluorodopa PET scans at North Shore University Hospital, patients have undergone a blinded surgical procedure at University of Colorado. Under local anesthesia, all patients have four burrholes through the forehead. In the active transplant group, cultured mesencephalic tissue from four embryos (ED 45-60) is implanted along four 30 to 40 mm needle tracts bilaterally in the putamen. Control patients have no needles penetrating brain. After surgery, blinded evaluations continue for one year. After the blind is broken, placebo surgery patients may elect a tissue implant. By June 1997, 31 of 40 patients have received either an implant or a sham procedure. A total of 24 patients have completed the 12 month followup and have had their blind revealed. All of the first eligible sham surgery patients have requested implant surgery. There have been no perioperative complications. One patient died in an automobile accident 7 months after fetal tissue implant. Immunocytochemical analysis for tyrosine hydroxylase has shown abundant dopamine cell survival in all four needle tracts with about 100,000 dopamine neurons surviving from the four embryos transplanted. Specific Aim 1 is to finish the blinded surgical procedures and the 12-month blinded evaluations of the randomized patients. Specific Aim 2 is to complete the unblinded implant surgeries on patients receiving initial placebo surgery and to follow all patients after unblinding for an additional 4 to 7 years. We postulate that transplant patients will show greater first year clinical improvement than placebo patients. In the long term, we predict that implant patients will show progressive improvement for several years after transplant. Our patient cohort is uniquely able to define the early and long term outcome of neurotransplantation.